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Cells Feb 2021Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Na1.4 sodium channel. Here, we...
Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Na1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen's disease. One novel mutation (p.W322*) in and one undescribed mutation (p.R1463H) in are segregating in this family. The -p.W322* was also found in an unrelated family, in compound heterozygosity with the known -p.G355R mutation. One reported mutation, -p.T1313M, was found in a third family. Both mutations exhibited loss-of-function: -p.W322* probably leads to a non-viable truncated protein; for -p.G355R, we predict structural damage, triggering important steric clashes. The -p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that -p.W322* and -p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients.
Topics: Chloride Channels; Female; Genetic Testing; Humans; Male; Middle Aged; Mutation; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree
PubMed: 33670307
DOI: 10.3390/cells10020374 -
Frontiers in Neurology 2020The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene () has expanded with advancements in genetic testing. Autosomal dominant...
The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene () has expanded with advancements in genetic testing. Autosomal dominant mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic variant, c.2386C>G p.L769V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another case of p.L769V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L769V is a pathogenic variant, that along with other cases in the literature, defines a new dominant disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.
PubMed: 32117035
DOI: 10.3389/fneur.2020.00077 -
BMC Medical Genetics Oct 2020Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can...
BACKGROUND
Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state.
CASE PRESENTATION
We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities.
CONCLUSIONS
Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.
Topics: Child; Chloride Channels; Electromyography; Genetic Predisposition to Disease; Humans; Male; Muscle Contraction; Muscle, Skeletal; Myotonia Congenita; Protein Isoforms
PubMed: 33092578
DOI: 10.1186/s12881-020-01128-5 -
Genes Feb 2022Congenital myopathy associated with pathogenic variants in the gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian...
Congenital myopathy associated with pathogenic variants in the gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient is a 17-year-old female with compound-heterozygous single nucleotide variants in the gene: c.862A>T, p.(Lys288Ter) and c.93del, p.(Lys32ArgfsTer78). She has a milder phenotype than the earlier described patients. To our knowledge, this is the first case of a patient who had both nonsense and frameshift variants. It is assumed that the frameshift variant with premature stop codon lead to nonsense-mediated RNA decay. However, there are two additional coding isoforms of the gene, which are not affected by this frameshift variant. We can speculate that these isoforms may partially carry out the function, and possibly explain the milder phenotype of our patient.
Topics: Cleft Palate; Female; Humans; Malignant Hyperthermia; Muscular Diseases; Myotonia Congenita
PubMed: 35205385
DOI: 10.3390/genes13020341 -
Turkish Journal of Anaesthesiology and... Aug 2019Anaesthetic management in paramyotonia congenita (PC) or 'paradoxical myotonia' poses perioperative challenges to the anaesthesiologists both in obstetric and...
Anaesthetic management in paramyotonia congenita (PC) or 'paradoxical myotonia' poses perioperative challenges to the anaesthesiologists both in obstetric and non-obstetric surgical patients. There are only a few case reports on the anaesthesia management particularly in the obstetric population. Therefore, we aimed to present the management of analgesia of labour and emergency caesarean delivery for a 26-year-old parturient with PC.
PubMed: 31380517
DOI: 10.5152/TJAR.2019.69094 -
Cureus Feb 2024Congenital myotonia represents a rare group of genetically inherited conditions. It can be either autosomal dominant (Thomsen) or autosomal recessive (Becker). It is...
Congenital myotonia represents a rare group of genetically inherited conditions. It can be either autosomal dominant (Thomsen) or autosomal recessive (Becker). It is characterized by muscular hypertrophy, proximal weakness, and myotonia, or impaired relaxation after contraction. These are due to mutations in the CLC1 gene. A 14-year-old male child presented with complaints of gradually progressive weakness for five years. Weakness was more pronounced in the proximal muscle groups. The weakness worsened after rest and improved with activity. This led to absenteeism and affected his school performance. Clinical examination showed generalized muscular hypertrophy with pronounced hypertrophy of the calf muscles. A neurological examination showed significant myotonia and impaired relaxation after making a fist. The diagnosis of myotonia was confirmed by electromyography, which produced a dive-bomber sound on insertion. Next-generation sequencing revealed a homozygous eight-base pair insertion in exon 19 of the CLCN1 gene. This mutation has not been reported in the existing literature for myotonia congenita. The child was started on mexiletine and improved significantly. Presently, the patient is on regular medications and doing well on follow-up. Though rare, congenital myotonia is an important cause of neuromuscular weakness. It can be easily diagnosed with a thorough clinical examination and routine testing for myotonia in all children with weakness. The treatment is relatively simple and can give the patient significant relief. Myotonia can be easily diagnosed clinically, and pharmacotherapy and proper monitoring can remarkably improve patients' quality of life.
PubMed: 38469025
DOI: 10.7759/cureus.53981 -
Scientific Reports Oct 2019Mutations in the CLCN1 gene are the primary cause of non-dystrophic Hereditary Myotonia in several animal species. However, there are no reports of Hereditary Myotonia...
Mutations in the CLCN1 gene are the primary cause of non-dystrophic Hereditary Myotonia in several animal species. However, there are no reports of Hereditary Myotonia in pigs to date. Therefore, the objective of the present study was to characterize the clinical and molecular findings of Hereditary Myotonia in an inbred pedigree. The clinical, electromyographic, histopathological, and molecular findings were evaluated. Clinically affected pigs presented non-dystrophic recessive Hereditary Myotonia. Nucleotide sequence analysis of the entire coding region of the CLCN1 gene revealed the absence of the exons 15 and 16 in myotonic animals. Analysis of the genomic region flanking the deletion unveiled a large intragenic deletion of 4,165 nucleotides. Interestingly, non-related, non-myotonic pigs expressed transcriptional levels of an alternate transcript (i.e., X2) that was identical to the deleted X1 transcript of myotonic pigs. All myotonic pigs and their progenitors were homozygous recessive and heterozygous, respectively, for the 4,165-nucleotide deletion. This is the first study reporting Hereditary Myotonia in pigs and characterizing its clinical and molecular findings. Moreover, to the best of our knowledge, Hereditary Myotonia has never been associated with a genomic deletion in the CLCN1 gene in any other species.
Topics: Animals; Base Sequence; Chloride Channels; Exons; Female; Heterozygote; Homozygote; Male; Myotonia Congenita; Pedigree; Sequence Deletion; Swine; Swine Diseases
PubMed: 31666547
DOI: 10.1038/s41598-019-51286-7 -
Biomedical Papers of the Medical... Dec 2019Paramyotonia congenita is a non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. This condition cannot be distinguished...
BACKGROUND
Paramyotonia congenita is a non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. This condition cannot be distinguished on the basis of symptoms and signs alone. It requires consideration of genetics as more than 100 mutations in the CLCN1 gene and at least 20 mutations in the SCN4A gene are associated with the clinical features of the non-dystrophic myotonias. Only a few families with the described features but no genetic testing have been reported in Slovakia. This prompted us to investigate genetic mutations in the SCN4A gene in 3 Slovak families clinically diagnosed with paramyotonia.
SUBJECTS AND METHODS
Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. SCN4A variants were screened by Sanger sequencing.
RESULTS
Our results revealed 2 potential disease-causing mutations present in the probands and affected family members - mutations c.3938C > T (p.T1313M) in two families and mutation c.2111C>T (p. T704M) in one family.
CONCLUSION
Our results may help to identify genetic determinants as well as clarify genotype-phenotype relationships in patients with paramyotonia in Slovakia.
Topics: Adolescent; Adult; Child; Child, Preschool; Chloride Channels; Female; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Infant; Male; Mutation; Myotonic Disorders; Pedigree; Phenotype; Slovakia; Young Adult
PubMed: 30647473
DOI: 10.5507/bp.2018.078 -
Neuromuscular Disorders : NMD Oct 2022This pilot study explored the feasibility and effectiveness of vibration therapy (VT) on muscle and bone health, motor performance, and respiratory function in patients...
This pilot study explored the feasibility and effectiveness of vibration therapy (VT) on muscle and bone health, motor performance, and respiratory function in patients with congenital myopathy (CM). Eleven participants with CM (11.5 ± 2.8 years) underwent 12 weeks of side-alternating VT at 20 Hz for nine minutes per session, four days a week. VT was preceded by a 12-week control period. Assessments included dual-energy X-ray absorptiometry scans, 6-minute walk and 10-meter run tests, muscle function and motor performance assessment, dynamometry, and pulmonary function. VT was well-tolerated, with occasional mild itchiness reported. The median compliance level with VT treatment was 75%. 12 weeks of VT improved the total score of motor function performance by 2.4 units (p=0.006) and velocity rise maximum of the chair rising test by 0.11 m/s (p=0.029). VT was shown to be feasible, safe, and associated with improving motor function performance. Our findings support further exploration of VT's potential health benefits to patients with CM in larger studies involving a longer intervention period.
Topics: Child; Humans; Adolescent; Vibration; Pilot Projects; Feasibility Studies; New Zealand; Muscular Diseases; Myotonia Congenita
PubMed: 35973877
DOI: 10.1016/j.nmd.2022.07.398 -
Medecine Sciences : M/S Nov 2019Congenital myopathies represent a quite heterogeneous group of neuromuscular disorders both at the clinical and genetic level. High-throughput sequencing (NGS), targeted...
Congenital myopathies represent a quite heterogeneous group of neuromuscular disorders both at the clinical and genetic level. High-throughput sequencing (NGS), targeted or not, combined with muscle pathology, greatly facilitate their accurate characterization and occasionally lead to unexpected discoveries like in the case reported here in a Kuwaiti family facing a long diagnostic odyssey.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Africa; Amino Acid Substitution; Black People; Child; Cleft Palate; DNA Mutational Analysis; Diagnosis, Differential; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Kuwait; Male; Malignant Hyperthermia; Mutation, Missense; Myotonia Congenita; Phenotype; Qatar; Saudi Arabia; Siblings
PubMed: 31859625
DOI: 10.1051/medsci/2019237